The heart responds to diverse stimuli by morphological and functional adaptation. The cardiac adaptive repertoire is stimulus-specific. For example, endurance exercise yields eccentric hypertrophy, while pressure overload or certain mutant sarcomeric proteins can provoke concentric hypertrophy. We will explore the pathways leading to these physiologic and pathologic adaptations and we will determine the potential roles of diet and sex in modifying them. The diagram at the left illustrates the overall goals of this proposal. We have recently found that substituting a casein-based diet for the traditional soy-based diet in a mouse model of hypertrophic cardiomyopathy (HCM) has profound and unexpected effects on pathogenesis. It therefore seems plausible that phytoestrogens in standard rodent chow dramatically affect disease and may also affect exercise adaptation; what is the mechanism of this effect? Genetic mouse models will be employed to ask the following questions: 1) which known signaling pathways play a role in HCM? 2) what role do those same pathways play in exercise adaptation? 3) how do sex and diet modify these adaptations? Mouse models that can potentially answer such questions are in hand: models of HCM with mutations in myosin heavy chain (MyHC) or cardiac troponin T (cTnT), and mice with alterations in cardiac signaling molecules. Genetic crosses among them will contribute to answering these questions. The signaling molecules and pathways that we have chosen to pursue include: CaMK, Akt, GSK3a, MEKK1, ERK1/2, JNK, p38 and MEF2. In order to extend our studies beyond these selected pathways and molecules, we will also assess global gene expression changes in the heart that occur between the sexes and how dietary and exercise interventions affect them. We feel that these approaches will be very useful to our understanding of the basic biology of adaptive and maladaptive cardiac hypertrophy and pathogenesis.